US8133909B2 - Heteroaromatic monoamides as orexinin receptor antagonists - Google Patents
Heteroaromatic monoamides as orexinin receptor antagonists Download PDFInfo
- Publication number
- US8133909B2 US8133909B2 US12/481,627 US48162709A US8133909B2 US 8133909 B2 US8133909 B2 US 8133909B2 US 48162709 A US48162709 A US 48162709A US 8133909 B2 US8133909 B2 US 8133909B2
- Authority
- US
- United States
- Prior art keywords
- phenyl
- ethyl
- pyridin
- trifluoromethyl
- acetamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
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Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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Definitions
- Orexins hypocretins
- hypothalamic neuropeptides a family of hypothalamic neuropeptides, play an important role in modulating feeding behavior, energy homeostasis and the sleep-wake cycle (Siegel, Annu. Rev. Psychol., 55, 125-148, 2004).
- the orexin-A/hypocretin1 (OX-A, 33 amino acids) and orexin-B/hypocretin2 (OX-B, 28 amino acids) are derived from the same precursor by proteolytic processing of 130 amino acids prepro-orexin (de Lecea et al., Proc Natl Acad Sci USA, 95, 322-327, 1998; Sakurai T. et al., Cell, 92, 573-585, 1998).
- orexin-1 receptor OX 1 R
- orexin-2 receptor OX 2 R
- OX 1 R OX 1 R
- OX 2 R orexin-2 receptor
- the characterization of both receptors in binding and functional assays demonstrated that OX 2 R is a non-selective receptor for both OX-A and -B, whereas OX 1 R is selective for OX-A, conversely OX-A is a non-selective neuropeptide and binds with similar affinities to OX 1 R and OX 2 R, while OX-B is selective and has a higher affinity for OX2R (Sakurai T. et al., Cell, 92, 573-585, 1998).
- Both receptors belong to the class A family of G-protein-coupled receptors (GPCRs) that couple via G q/11 to the activation of phospholipase C leading to phosphoinositide (PI) hydrolysis and elevation of intracellular Ca 2+ levels.
- GPCRs G-protein-coupled receptors
- OX2R could also couple via G i/o to cAMP pathway (Sakurai, Regulatory Peptides, 126, 3-10, 2005).
- Northern blot analysis of adult rat tissues showed that the prepro-orexin mRNA is detected exclusively in the brain (except for a small amount in the testis) and that the OX 1 R and OX 2 R transcripts are also exclusively detected in the brain (Sakurai T.
- a disrupted orexin system is suggested to be the cause of narcolepsy based on following lines of evidence: (a) Prepro-orexin knockout mice possessed a phenotype with characteristics remarkably similar to narcolepsy (Chemelli et al., Cell, 98, 437-451, 1999), (b) a mutation (canarc-1), which disrupts the gene encoding OX 2 R, was found to be responsible for canine narcolepsy (Lin et al., Cell, 98, 365-376, 1999), (c) lack of OX-A and OX-B was observed in human narcoleptic patients (Nishino et al., Lancet, 355, 39-40, 2000; Peyron et al., Nature Medicine, 6, 991-997, 2000), (d) it has been shown that Modafinil, an anti-narcoleptic drug with unknown mechanism of action, activates orexin neurons (Mignot et al., Sleep,
- Orexin plays an important role in stress and anxiety via its interaction with the corticotropin-releasing factor (CRF) system in hypothalamus (Sakamoto et al., Regul Pept., 118, 183-91, 2004).
- CRF corticotropin-releasing factor
- the icv injection of OX-A induces grooming (stress-response) which is blocked in part by a CRF antagonist (Ida et al., Biochem. Biophys. Res. Comm., 270, 318-323, 2000).
- OX 2 R is highly expressed in adrenal medulla, whereas OX 1 R is high in adrenal cortex.
- OX-A and OX-B stimulate corticosterone release in plasma and induce c-Fos in paraventricular nucleus (PVN) in the hypothalamus (Kuru et al., Neuroreport, 11, 1977-1980, 2000). Furthermore, orexin neurons projecting to CRF neurons express mainly the OX 2 R (Winsky-Sommerer et al., J. Neuroscience, 24, 11439-11448, 2004). Therefore, OX2R stimulation activates the hypothalamo-pituitary-adrenal (HPA) axis.
- HPA hypothalamo-pituitary-adrenal
- the present invention provides compounds of formula
- the invention also provides pharmaceutical compositions containing compounds of formula I.
- the invention further provides processes for the manufacture of the compounds and compositions of the invention.
- Compounds of formula I are orexin receptor antagonists and the related compounds may be useful in the treatment of disorders, in which orexin pathways are involved like sleep disorders including sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, circadian rhythms disorder, restless leg syndrome, psychiatric, neurological and neurodegenerative disorders including anxiety, depression, manic depression, obsessive compulsive disorders, affective neurosis, depressive neurosis, anxiety neurosis, mood disorder, delirium, panic-attack disorder, posttraumatic stress disorders, sexual dysfunction, schizophrenia, psychosis, cognitive disorders, Alzheimer's and Parkinson's diseases, dementia, mental retardation, dyskinesias such as Huntington's disease and Tourette syndrome, addictions, craving associated with drug abuse, seizure disorders, epilepsy, metabolic diseases such as obesity, diabetes, eating disorders including anorexia and bulimia, asthma, migraine, headache pain, neuropathic pain, sleep disorders associated with psychiatric, neurological and neurodegenerative
- alkyl denotes a straight- or branched-chain hydrocarbon group containing from 1-7 carbon atoms.
- the term “lower alkyl” denotes a straight- or branched-chain alkyl group containing from 1-4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
- halogen denotes chlorine, iodine, fluorine and bromine.
- lower alkyl substituted by halogen denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CH 2 CF 3 , CH 2 CF 2 CF 3 and the like.
- Preferred lower alkyl substituted by halogen are lower alkyl substituted by fluoro.
- lower alkyl substituted by hydroxy denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by hydroxy, for example CH 2 ,OH or CH 2 CH 2 OH.
- lower alkoxy denotes a lower alkyl group as defined above, which is attached via an oxygen atom.
- lower alkoxy substituted by halogen denotes a lower alkoxy group as defined above, wherein at least one hydrogen atom is replaced by a halogen residue, such as OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CF 3 , OCH 2 CH 2 CF 3 , OCH 2 CF 2 CF 3 and the like.
- Preferred lower alkoxy substituted by halogen are lower alkoxy substituted by fluoro.
- cycloalkyl denotes a saturated carbocyclic group, containing 3-6 carbon atoms.
- lower alkyl substituted by cycloalkyl denotes a lower alkyl group as defined above, wherein one hydrogen atom is replaced by a cycloalkyl group, for example CH 2 -cyclopropyl, CH 2 -cyclobutyl, CH 2 -cyclopentyl or CH 2 -cyclohexyl.
- aryl means the monovalent cyclic aromatic hydrocarbon group consisting of one or more fused rings in which at least one ring is aromatic in nature.
- aryl radicals include, but are not limited to, phenyl, naphthyl, 5,6,7,8-tetrahydro-naphthalenyl, biphenyl, indanyl, anthraquinolyl, and the like.
- a preferred aryl group is phenyl.
- Heteroaryl means a cyclic group having one or more rings, wherein at least one ring is aromatic in nature, incorporating one, two, or three heteroatoms within the ring (chosen from nitrogen, oxygen, and sulfur).
- heteroaryl radicals include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiophenyl, furanyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzopyranyl, indazolyl, indolyl, isoindolyl, chromanyl, naphtyridinyl, 2,3-dihydro-
- Heterocycloalkyl means a monovalent saturated moiety, consisting of one, two or three rings, incorporating one, two, or three heteroatoms (chosen from nitrogen, oxygen and sulfur). Heterocycloalkyl can optionally be substituted with one, two, three or four substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, or carbonylamino, unless otherwise specifically indicated.
- heterocyclic moieties include, but are not limited to, optionally substituted tetrahydro-furanyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, and the like or those which are specifically exemplified herein.
- “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
- pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
- “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
- the invention provides a compound of formula IB
- the invention provides a compound of formula IC
- Preferred compounds as defined above are those, wherein R 1 is hydrogen, halogen, lower alkyl or lower alkyl substituted by fluoro, more preferably wherein R 1 is methyl, trifluoromethyl, fluoro or chloro.
- R 2 is hydrogen, halogen or lower alkoxy, more preferably wherein R 2 is hydrogen, fluoro or chloro.
- R 3 is hydrogen, halogen, cyano, lower alkyl, lower alkyl substituted by fluoro, lower alkyl substituted by hydroxy, lower alkoxy, lower alkoxy substituted by fluoro, C(O)O-lower alkyl, C(O)NH-lower alkyl or cycloalkyl. More preferably, R 3 is hydrogen, halogen, lower alkyl, lower alkyl substituted by hydroxy, lower alkoxy, lower alkoxy substituted by fluoro or C(O)O-lower alkyl. Even more preferably, R 3 is hydrogen, methyl, methoxy, fluoro, chloro, hydroxymethyl, difluoromethoxy or C(O)OCH 3 .
- Still other preferred compounds are those, wherein R 4 is hydrogen or lower alkyl, particularly wherein R 4 is hydrogen or methyl.
- R 5 is hydrogen, NH 2 , hydroxy, lower alkyl, NHC(O)CH(NH 2 )-phenyl, NH(oxetan-3-yl), NH(3-(CH 2 NH 2 )-oxetan-3-yl) 2 , NH—SO 2 -lower alkyl, NH-cycloalkyl, OC(O)-lower alkyl or CH 2 NH 2 .
- R 5 is hydrogen, NH 2 , hydroxy, CH 3 , NHC(O)CH(NH 2 )-phenyl, NH(oxetan-3-yl), NH(3-(CH 2 NH 2 )-oxetan-3-yl) or OC(O)—CH 3 . Furthermore, it is preferred that R 4 and R 5 together are ⁇ O.
- heteroaryl preferably is pyridinyl, thiazolyl, thienyl or isoxazolyl. More preferably, said heteroaryl is pyridine-2-yl, pyridine-3-yl, thiazol-2-yl or isoxazol-5-yl.
- Ar 2 is heteroaryl
- said heteroaryl preferably is pyridinyl, thiazolyl, benzothiazolyl, pyrazolyl, indazolyl, quinolinyl, benzooxazolyl or indolyl. More preferably, said heteroaryl is pyridine-3-yl, thiazol-5-yl, pyrazol-3-yl, indazol-5-yl, quinolin-3-yl or indol-3-yl.
- Ar is heteroaryl
- said heteroaryl preferably is pyridinyl or benzoimidazolyl.
- Ar is phenyl.
- n preferably is 1.
- p preferably is 1.
- o preferably is 1 or 2.
- Preferred compounds of formula IA are the following:
- Preferred compounds of formula IB are the following:
- Preferred compounds of formula IC are the following:
- present compounds of formula IA, IB and IC and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises reacting a compound of formula IIA, IIB or IIC
- a coupling-reagent e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride
- a coupling-reagent e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride
- R 1 -R 5 , n, o and p m are as described above, and, if desired, converting a compound of formula IA, IB or IC into a pharmaceutically acceptable salt.
- a compound of formula IIA can be prepared as follows:
- Carboxylic acid IV and aniline V are stirred in a suitable solvent, for example dichloromethane, with 1-hydroxybenzotriazole (HOBT) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in the presence of a suitable base, for example N,N-diisopropylethylamine, at ambient or elevated temperature.
- a suitable solvent for example dichloromethane
- HOBT 1-hydroxybenzotriazole
- EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- a suitable base for example N,N-diisopropylethylamine
- aniline IIA can be obtained by stirring of nitrile VI and aniline V in a suitable solvent, for example methanol, with ammonium acetate and palladium on charcoal at ambient or elevated temperature.
- a suitable solvent for example methanol
- heating of aniline V with the vinyl-compound VII in the presence of cesium hydroxide in a suitable solvent, for example N-methylpyrrolidine affords the desired aniline IIA.
- IIA can be obtained by heating of amine VII and aryl-halogenide IX in the presence of copper(I) iodide and 2-acetylcyclohexanone in a suitable solvent, for example N,N-dimethylformamide.
- a compound of formula IA can be prepared as follows:
- a compound of formula IA can be prepared as follows:
- a compound of formula IA can be prepared as follows:
- a compound of formula IA can be prepared as follows:
- Carboxylic acid XIV and amine XV are stirred in a suitable solvent, for example dichloromethane, with 1-hydroxybenzotriazole (HOBT) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in the presence of a suitable base, for example N,N-diisopropylethylamine, at ambient or elevated temperature.
- a suitable base for example N,N-diisopropylethylamine
- the reaction mixture is then concentrated and heated with borane-tetrahydrofuran complex in a suitable solvent, for example tetrahydrofuran, at elevated temperature to afford IIB.
- IIB can be obtained by heating of amine XII and heteroaryl-halogenide XVII in the presence of a base, for example potassium carbonate, in a suitable solvent, for example dimethylsulfoxid.
- a compound of formula IB can be prepared as follows:
- a compound of formula IB can be prepared as follows:
- a compound of formula IB can be prepared as follows:
- a compound of formula IB can be prepared as follows:
- a compound of formula IIC can be prepared as follows:
- Amine IIC can be obtained by stirring of nitrile VI and amine XV in a suitable solvent, for example methanol, with ammonium acetate and palladium on charcoal at ambient or elevated temperature (according to scheme 15).
- a suitable solvent for example methanol
- a compound of formula IC can be prepared as follows:
- the Chinese Hamster Ovary (dHFr—) mutant cell line stably expressing human orexin-1 (hOX1) or human orexin-2 (hOX2) receptors were maintained in Dulbecco's Modified Eagle Medium (1X) with GlutaMaxTM 1, 4500 mg/L D-Glucose and Sodium Pyruvate (Catalog No. 31966-021, Invitrogen, Carlsbad, Calif.), 5% dialyzed fetal calf serum (Catalog No. 26400-044), 100 ⁇ g/ml penicillin and 100 ⁇ g/ml streptomycin.
- the cells were seeded at 5 ⁇ 10 4 cells/well in the poly-D-lysine treated, 96-well, black/clear-bottomed plates (Catalog No. BD356640, BD Biosciences, Palo Alto, Calif.). 24 h later, the cells were loaded for 1 h at 37° C. with 4 ⁇ M Flou-4 acetoxymethyl ester (Catalog No. F-14202, Molecular Probes, Eugene, Oreg.) in FLIPR buffer (1 ⁇ HBSS, 20 mM HEPES, 2.5 mM Probenecid). Hanks' Balanced Salt Solution (HBSS) (10 ⁇ ) (catalog No. 14065-049) and HEPES (1M) (catalog No.
- Orexin A (50 mM stock solution in DMSO) was diluted in FLIPR buffer +0.1% BSA.
- the EC 50 and EC 80 values of orexin-A were measured daily from standard agonist concentration-response curves in CHO(dHFr—)—OX1R and —OX2R cell lines. All compounds were dissolved in 100% DMSO. Inhibition curves were determined by addition of 11 concentrations (0.0001-10 ⁇ M) of inhibitory compounds and using EC 80 value of orexin-A as agonist (a concentration which gave 80% of max agonist response, determined daily). The antagonists were applied 25 min (incubation at 37° C.) before the application of the agonist.
- the present invention also provides pharmaceutical compositions containing compounds of the invention, for example, compounds of formula I or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
- Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions.
- the pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
- compositions of the invention in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier.
- suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules.
- Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules.
- Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
- Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
- compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- the present invention also provides a process for the manufacture of pharmaceutical compositions. Such process comprises bringing the compound of formula I and/or pharmaceutically acceptable acid addition salt thereof and, fir desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
- the most preferred indications in accordance with the present invention are those, which include sleep disorders including sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, circadian rhythms disorder, restless leg syndrome, psychiatric, neurological and neurodegenerative disorders including anxiety, depression, manic depression, obsessive compulsive disorders, affective neurosis, depressive neurosis, anxiety neurosis, mood disorder, delirium, panic-attack disorder, posttraumatic stress disorders, sexual dysfunction, schizophrenia, psychosis, cognitive disorders, Alzheimer's and Parkinson's diseases, dementia, mental retardation, dyskinesias such as Huntington's disease and Tourette syndrome, addictions, craving associated with drug abuse, seizure disorders, epilepsy, metabolic diseases such as obesity, diabetes, eating disorders including anorexia and bulimia, asthma, migraine, pain, neuropathic pain, sleep disorders associated with psychiatric, neurological and neurodegenerative disorders, neuropathic pain, enhanced or exaggerated sensitivity to pain such
- the dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
- the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
- the daily dosage can be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
- Tablet Formulation mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831 Manufacturing Procedure
- Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148 — 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600 Manufacturing Procedure
- the resulting brown reaction mixture was concentrated in vacuo, diluted with TBME (50 mL) and cooled to 0° C. before aqueous NaHCO 3 (1M, 100 mL) was added. The mixture was stirred for 30 min., the aqueous layers were extracted with TBME (50 mL) and the combined organic layers were washed with aqueous NaHCO 3 (1M, 50 mL) and brine (50 mL). Drying over sodium sulphate was followed by concentration. The resulting oil (6.44 g) was dissolved in DMSO (15 mL) and sodium cyanide (1.36 g, 27.8 mmol) was added.
- reaction mixture was concentrated and a solution of borane-tetrahydrofuran complex (1 M in THF, 5 mL, 5 mmol) was added and the reaction mixture was stirred for 18 h at 60° C. A further portion of the borane-tetrahydrofuran complex (1 M in THF, 5 mL, 5 mmol) was added and the reaction mixture was stirred for 4 h at 80° C. An aqueous solution of hydrochloric acid (1 M, 2 mL) was carefully added and stirring was continued for 15 min. at reflux.
- step 2 1,3-dimethyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-1,3-dihydrobenzoimidazol-2-one (80 mg, 0.228 mmol) was coupled to t-BOC-L-phenylglycine (80 mg, 0.32 mmol) to afford the title compound (58 mg, 5 3%) as a light yellow oil. MS m/e: 484.2 [M+H] + .
- step 1 (5,6,7,8-tetrahydro-naphthalen-2-yl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (250 mg, 0.78 mmol, prepared as described in example 9, step 1) and benzoylformic acid (141 mg, 0.939 mmol) were coupled to provide the title compound (355 mg, 100%) as a yellow oil which was used without further purification in the next step.
- step 1 4-methylaniline (298 mg, 2.78 mmol) was coupled to (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (750 mg, 4.03 mmol) to provide the title compound as a pale yellow oil (392 mg, 35%) MS m/e: 281.1 [M+H] + .
- step 2 The racemic alcohol from example 14, step 2 was separated by chromatography on a chiral column to give the title compound as a colourless oil which crystallized on standing (95 mg, 31.5%) MS m/e: 415.1 [M+H] + .
- step 4 (without TFA addition), (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (prepared in example 1, step 3) was coupled to phenylacetic acid to provide the title compound as a pale yellow oil. MS m/e: 413.2 [M+H]+.
- step 1 2-methoxy-1-methyl-4-nitro-benzene (988 mg, 5.91 mmol) was coupled to (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (1.0 g, 5.37 mmol, prepared in example 1, step 1) to give the title compound (521 mg, 31%) as an orange oil MS m/e: 311.1 [M+H] + .
- the resulting brown reaction mixture was concentrated in vacuo, diluted with TBME (50 mL) and cooled to 0° C. before aqueous NaHCO 3 (1M, 100 mL) was added. The mixture was stirred for 30 min., the aqueous layers were extracted with TBME (50 mL) and the combined organic layers were washed with aqueous NaHCO 3 (1M, 50 mL) and brine (50 mL). Drying over sodium sulfate was followed by concentration. The resulting oil (6.44 g) was dissolved in DMSO (15 mL) and sodium cyanide (1.36 g, 27.8 mmol) was added.
- step 3 the title compound was prepared from (3,4-dimethyl-phenyl)-(2-pyridin-2-yl-ethyl)-amine and boc-L-alpha-phenylglycine. MS (m/e): 460.3 [M+H] + .
- step 4 the title compound was prepared from ⁇ (S)-[(3,4-dimethyl-phenyl)-(2-pyridin-2-yl-ethyl)-carbamoyl]-phenyl-methyl ⁇ -carbamic acid tert-butyl ester. MS (m/e): 360.2 [M+H] + .
- step 1 the title compound was prepared from 4-iodo-o-xylene and 2-pyridin-3-yl-ethylamine (CAS: 20173-24-4). MS (m/e): 227.2 [M+H] + .
- step 3 the title compound was prepared from (3,4-dimethyl-phenyl)-(2-pyridin-3-yl-ethyl)-amine and boc-L-alpha-phenylglycine. MS (m/e): 460.3 [M+H] + .
- step 4 the title compound was prepared from ⁇ (S)-[(3,4-dimethyl-phenyl)-(2-pyridin-3-yl-ethyl)-carbamoyl]-phenyl-methyl ⁇ -carbamic acid tert-butyl ester. MS (m/e): 360.4 [M+H] + .
- step 3 the title compound was prepared from (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (example 20, step 3) and S(+)-2-phenylpropionic acid. MS (m/e): 427.3 [M+H] + .
- step 3 the title compound was prepared from (3,4-dimethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine and boc-L-alpha-phenylglycine. MS (m/e): 528.3 [M+H] + .
- step 4 the title compound was prepared from ((S)- ⁇ (3,4-dimethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-carbamoyl ⁇ -phenyl-methyl)-carbamic acid tert-butyl ester. MS (m/e): 428.1 [M+H] + .
- aqueous ammonium chloride (20% (w/w), 5 mL was added and the organig layer separated and washed with brine (15 mL). The aqueous layers were extracted with TBME (15 mL) and the combined organic layers were dried over sodium sulfate.
- step 2 the title compound was prepared from (R,S)-methanesulfonic acid phenyl- ⁇ (5,6,7,8-tetrahydro-naphthalen-2-yl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-carbamoyl ⁇ -methyl ester and cyclobutylamine.
- the reaction mixture was diluted with dichloromethane (20 mL) and washed with aqueous sodium carbonate (half-concentrated, 20 mL) and water (20 mL). The aqueous layers were extracted with dichloromethane (20 mL) and the combined organic layers were dried over sodium sulfate. The filtrate was concentrated and the residue was suspended in TBME (20 mL) and filtered. Washing with TBME (10 mL) afforded the title compound (1.48 g, 90%) as a white solid. MS m/e: 247.2 [M+H] + .
- reaction mixture was concentrated and a solution of borane-tetrahydrofuran complex (1 M in THF, 3 eq.) was added and the reaction mixture was stirred for 18 h at 60° C. A further portion of the borane-tetrahydrofuran complex (1 M in THF, 3 eq.,) was added and the reaction mixture was stirred for 4 h at 80° C. An aqueous solution of hydrochloric acid (1 M, 2 mL) was carefully added and stirring was continued for 15 min. at reflux. After cooling it was diluted with ethyl acetate (15 mL) and washed with aqueous Na 2 CO 3 (saturated, 15 mL).
- step 2 without TFA addition, (6-methoxy-pyridin-3-yl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine, prepared in example 33, step 1) was coupled to (2-methoxy-phenyl)-acetic acid (commercially available) to give the title compound. MS m/e: 445.3 [M+H] + .
- step 1 (4-trifluoromethyl-phenyl)-acetic acid (commercially available) was coupled with benzothiazol-6-ylamine (commercially available) to give the title compound.
- step 2 without TFA addition, benzothiazol-6-yl-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine was coupled to (2-methoxy-phenyl)-acetic acid (commercially available) to provide the title compound.
- step 1 (4-trifluoromethyl-phenyl)-acetic acid (commercially available) was coupled with 6-trifluoromethyl-pyridin-3-ylamine (commercially available) to give the title compound MS m/e: 335.1 [M+H] + .
- step 1 (4-trifluoromethyl-phenyl)-acetic acid (commercially available) was coupled with 2-methoxy-pyridin-3-ylamine (commercially available) to give the title compound.
- step 1 the title compound (2,4-dimethyl-thiazol-5-yl)-(2-p-tolyl-ethyl)-amine (MS m/e: 247.0 [M+H] + ) was prepared from 5-bromo-2,4-dimethyl-1,3thiazole and 2-(p-tolyl)ethylamine.
- step 2 the title compound (R,S)- ⁇ (4-Chloro-phenyl)-[(2,4-dimethyl-thiazol-5-yl)-(2-p-tolyl-ethyl)-carbamoyl]-methyl ⁇ -carbamic acid tert-butyl ester (MS m/e: 514.0 [M+H] + ) was prepared from (2,4-dimethyl-thiazol-5-yl)-(2-p-tolyl-ethyl)-amine and N-BOC-(4′-chlorophenyl)glycine.
- step 1 the title compound N-(6-chloro-pyridin-3-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 241.2 [M+H] + ) was prepared from 6-chloro-pyridin-3-ylamine and benzoylformic acid chloride.
- step 1 the title compound N-(6-methyl-pyridin-3-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 241.2 [M+H] + ) was prepared from 6-methyl-pyridin-3-ylamine and benzoylformic acid chloride.
- step 1 the title compound N-(6-chloro-pyridin-3-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 261.0 [M+H] + ) was prepared from 6-chloro-pyridin-3-ylamine and benzoylformic acid chloride.
- step 1 the title compound N-(2-methyl-pyridin-4-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 241.2 [M+H] + ) was prepared from 4-amino-2-picoline and benzoylformic acid chloride.
- the resulting brown reaction mixture was concentrated in vacuo, diluted with TBME (50 mL) and cooled to 0° C. before aqueous NaHCO 3 (1M, 100 mL) was added. The mixture was stirred for 30 min., the aqueous layers were extracted with TBME (50 mL) and the combined organic layers were washed with aqueous NaHCO 3 (1M, 50 mL) and brine (50 mL). Drying over sodium sulphate was followed by concentration. The resulting oil (6.44 g) was dissolved in DMSO (15 mL) and sodium cyanide (1.36 g, 27.8 mmol) was added.
- step 3 (1-ethyl-3-methyl-1H-indazol-5-yl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (100 mg, 0.287 mmol) was coupled to (S)-(+)-O-acetyl-L-mandelic acid (59 mg, 0.304 mmol) to give the title compound (179 mg, >100%) which was carried through to the next step without further purification.
- steps 2, 3 & 4 6-Methyl-pyridin-3-ylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (4-Fluoro-phenyl)-oxo-acetic acid were successively coupled and reduced to give after separation by chromatography on a chiral column (+ve rotation) the target compound.
- 6-Amino-chroman-4-ol (as described in WO 2005037830), (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled then hydrolysed to give the target compound.
- 6-Amino-chroman-4-ol (WO 2003063794), (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled then hydrolysed to give after silica gel chromatography the target compound. MS(m/e): 473.1 [M+H] + .
- 6-Amino-chroman-4-ol (WO 2003063794), (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled then hydrolysed to give after silica gel chromatography the target compound. MS(m/e): 473.1 [M+H] + .
- step 1 the title compound was prepared from (3,4-dimethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (example 25, step 1) and (S)-(+)-O-acetyl-L-mandelic acid. MS(m/e): 471.2 [M+H] + .
- step 1 and 26 step 1-2 [2-(5-Chloro-pyridin-2-yl)-ethyl]-(3,4-dimethyl-phenyl)-amine obtained by reacting 5-Chloro-2-vinyl-pyridine (CAS: 223445-06-5) with 3,4-dimethylaniline was coupled with (S)-(+)-O-acetyl-L-mandelic acid then hydrolysed to provide the title compound. MS(m/e): 395.1 [M+H] + .
- step 1-4 the title compound was prepared from 3,4-dimethylaniline and 4-methylthiazol-2-yl)-acetic acid (commercial). MS(m/e): 380.3 [M+H] + .
- step 1 and 26 step 1-2 (3,4-dimethyl-phenyl)-[2-(5-fluoro-pyridin-2-yl)-ethyl]-amine obtained by reacting 5-Fluoro-2-vinyl-pyridine (CAS: 869108-71-4) with 3,4-dimethylaniline was coupled with (S)-(+)-O-acetyl-L-mandelic acid then hydrolysed to provide the title compound. MS(m/e): 379.3 [M+H] + .
- step 1 and 26 step 1-2 (3,4-dimethyl-phenyl)-(2-thiophen-3-yl-ethyl)-amine obtained by reacting 2-thiophen-3-yl-ethylamine (commercial) with 4-iodo-o-xylene (commercial) was coupled with (S)-(+)-O-acetyl-L-mandelic acid then hydrolysed to provide the title compound.
- step 1-2 and 26 step 1-2 the title compound was prepared from 3,4-dimethylaniline and 3-methyl-5-isoxazole acetic acid (commercial). MS(m/e): 365.2 [M+H] + .
- step 1 the title compound Indan-5-yl-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 307.2 [M+H] + ) was prepared from 5-amino-indan instead of 3,4-dimethylaniline and 5-trifluoromethyl-2-vinyl-pyridine.
- step 1 the title compound (R,S)-Acetic acid (4-fluoro-phenyl)- ⁇ indan-5-yl-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-carbamoyl ⁇ -methyl ester (MS m/e: 501.1 [M+H] + ) was prepared from indan-5-yl-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine instead of (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine and (R,S)-acetoxy-(4-fluoro-phenyl)-acetic acid instead of (4-fluoro-phenyl)-oxo-acetic acid.
- step 1 the title compound (4-isopropyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 309.2 [M+H] + ) was prepared from 4-isopropylaniline instead of 3,4-dimethylaniline and 5-trifluoromethyl-2-vinyl-pyridine.
- step 1 the title compound (2,3-dihydro-benzofuran-5-yl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 309.0 [M+H] + ) was prepared from 5-bromo-2,3-dihydro-1-benzofuran instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 1 the title compound (3-methoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 297.2 [M+H] + ) was prepared from 3-bromo-anisol instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 1 the title compound (3-fluoro-4-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 299.3 [M+H] + ) was prepared from 4-bromo-2-fluorotoluene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 1 the title compound (4-chloro-3-methoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 331.1 [M+H] + ) was prepared from 5-bromo-2-chloro-anisol instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 1 the title compound (4-ethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 295.2 [M+H] + ) was prepared from 1-bromo-4-ethyl-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 1 the title compound 4-methyl-6-[2-(5-trifluoromethyl-pyridin-2-yl)-ethylamino]-4H-benzo[1,4]oxazin-3-one (MS m/e: 352.2 [M+H] + ) was prepared from 6-bromo-4-methyl-4H-benzo[1,4]oxazin-3-one instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 2 the title compound (R,S)-2-(4-fluoro-phenyl)-2-hydroxy-N-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-N-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-acetamide (MS m/e: 504.1 [M+H] + ) was prepared from 4-methyl-6-[2-(5-trifluoromethyl-pyridin-2-yl)-ethylamino]-4H-benzo[1,4]oxazin-3-one instead of (4-fluoro-3-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine.
- step 1 the title compound 1-methyl-6-[2-(5-trifluoromethyl-pyridin-2-yl)-ethylamino]-3,4-dihydro-1H-quinolin-2-one (MS m/e: 350.3 [M+H] + ) was prepared from 6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 2 the title compound (R,S)-2-(4-fluoro-phenyl)-2-hydroxy-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-N-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-acetamide (MS m/e: 502.1 [M+H] + ) was prepared from 1-methyl-6-[2-(5-trifluoromethyl-pyridin-2-yl)-ethylamino]-3,4-dihydro-1H-quinolin-2-one instead of (4-fluoro-3-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine.
- step 1 the title compound (4-fluoro-3-methoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 315.1 [M+H] + ) was prepared from 5-bromo-2-fluoro-anisole instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 1 the title compound (4-cyclopropyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 307.2 [M+H] + ) was prepared from 1-bromo-4-cyclopropyl-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 1 the title compound (4-bromo-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 347.0 [M+H] + ) was prepared from 1-bromo-4-iodo-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 1 the title compound (2,2-dioxo-2,3-dihydro-1H-2lambda(6)-benzo[c]thiophen-5-yl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 357.1 [M+H] + ) was prepared from 5-amino-2,3-dihydro-1H-2lambda(6)-benzo[c]thiophene-2,2-dione instead of 3,4-dimethylaniline and 5-trifluoromethyl-2-vinyl-pyridine.
- step 1 the title compound (3-difluoromethoxy-4-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 347.1 [M+H] + ) was prepared from 4-iodo-2-difluoromethoxy-toluene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
- step 1 the title compound (3,4-bis-difluoromethoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 399.1 [M+H] + ) was prepared from 1,2-bis-difluoromethoxy-4-iodo-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
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US9480695B2 (en) | 2011-09-29 | 2016-11-01 | The University Of Tokyo | Methods for inducing orexin neurons and agent for treating narcolepsy or eating disorder |
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KR101884434B1 (ko) * | 2011-12-02 | 2018-08-02 | (주)아모레퍼시픽 | 한라송이풀 추출물을 함유하는 피부 외용제 조성물 |
BR112014019426A8 (pt) | 2012-02-07 | 2017-07-11 | Eolas Therapeutics Inc | Prolinas/ piperidinas substituídas como antagonistas do receptor de orexina |
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AU2009259494A1 (en) | 2009-12-23 |
EP2297102A1 (en) | 2011-03-23 |
KR20110025915A (ko) | 2011-03-14 |
US20090312314A1 (en) | 2009-12-17 |
CA2726703A1 (en) | 2009-12-23 |
CN102066325A (zh) | 2011-05-18 |
MX2010013192A (es) | 2010-12-17 |
JP2011524398A (ja) | 2011-09-01 |
WO2009153180A1 (en) | 2009-12-23 |
IL209264A0 (en) | 2011-01-31 |
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